Ibrutinib Before and After Stem Cell Transplant in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

Summary

Description

Summary

This randomized phase III trial studies ibrutinib to see how well it works compared to placebo when given before and after stem cell transplant in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Before transplant, stem cells are taken from patients and stored. Patients then receive high doses of chemotherapy to kill cancer cells and make room for healthy cells. After treatment, the stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. Ibrutinib is a drug that may stop the growth of cancer cells by blocking a protein that is needed for cell growth. It is not yet known whether adding ibrutinib to chemotherapy before and after stem cell transplant may help the transplant work better in patients with relapsed or refractory diffuse large B-cell lymphoma.

Official Title

A Randomized Double-Blind Phase III Study of Ibrutinib During and Following Autologous Stem Cell Transplantation Versus Placebo in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma of the Activated B-Cell Subtype

Details

PRIMARY OBJECTIVES:

To evaluate the ability of ibrutinib to improve 24-month progression free survival (PFS) compared to placebo.

SECONDARY OBJECTIVES:

To evaluate the ability of ibrutinib to improve overall survival (OS) compared to placebo.

II. To evaluate the ability of ibrutinib to improve progression free survival (PFS) compared to placebo.

III. To evaluate the ability of ibrutinib to improve post-transplant response rates compared to placebo.

IV. To evaluate time to hematopoietic recovery in the two arms. V. To evaluate the safety and tolerability of ibrutinib compared to placebo. VI. To evaluate the incidence of secondary malignancies in the two arms. VII. To evaluate immune reconstitution in the two arms.

III. To evaluate the application of the Lugano criteria and change in quantitative measurements between pre-AutoHCT and post AutoHCT (e.g. delta standard uptake variable [SUV], %SUV decline and %metabolic tumor volume [MTV] decline, and other available applicable quantitative measurements) to assess the association between changes in these variables and outcomes, such as PFS and OS.

IV. To assess whether the GSTT1 null polymorphism is correlated with pulmonary toxicity after BCNU (carmustine)-containing conditioning regimens as part of autologous stem cell transplantation.

To assess whether other polymorphisms in the BCNU metabolism pathway or BCNU damage repair pathway(s) are associated with pulmonary toxicity after BCNU-containing conditioning regimens as part of autologous stem cell transplantation.

VI. To evaluate whether any of the proposed deoxyribonucleic acid (DNA) polymorphisms are associated with other toxicities.

VII. To assess whether activating mutations in the BCR pathway are associated with response to ibrutinib and with clinical outcomes in patients treated on this protocol.

VIII. To assess whether there are any phenotypic associations with immunohistochemistry (IHC) markers (particularly MYC protein expression level) and presence of these mutations.

IX. To assess whether BCL2, MYC, and Ki67 expression by IHC affect clinical outcomes in patients treated on this protocol.

To assess whether translocations in MYC with or without BCL2 and BC6 have poor outcomes in patients treated on this protocol and whether ibrutinib modifies the prognosis.

BEAMi: Patients receive ibrutinib orally (PO) on days -6 to -1, carmustine intravenously (IV) over 2 hours on day -6, etoposide IV twice daily (BID) over 1-2 hours and cytarabine IV BID over 1-2 hours on days -5 to -2, and melphalan IV over 20-30 minutes on day -1.

CBVi: Patients receive ibrutinib PO on days -6 to -1, carmustine IV over 2 hours on day -6, etoposide IV over 4 hours on day -4, and cyclophosphamide IV on day -2.

ARM II: Patients receive placebo PO on days -6 to -1 and receive 1 of the 2 conditioning regimens as in Arm I.

Eligibility

For people ages 18 years and up

Inclusion Criteria:

PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0)

Patients must have paraffin tissue from the diagnostic or relapse biopsy available to be submitted for central pathology review and integral molecular subtyping; this review is mandatory prior to registration to confirm eligibility and should be initiated as soon as possible; determination of cell-of-origin subtype will be performed using the lymphoma subtyping test (LST) assay

ELIGIBILITY CRITERIA (STEP 1)

Diagnosis of World Health Organization (WHO) diffuse large B-cell lymphoma, high grade B-cell lymphoma not otherwise specified, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma

Patient must be deemed eligible to proceed with high-dose chemotherapy and autologous stem cell transplantation by local transplant center

New York Heart Association class I or less; ordinary physical activity does not cause undue fatigue, palpitations, dyspnea, or angina pain; patients 60 years or older must have a left ventricular ejection fraction (LVEF) at rest >= 40% measured by echocardiogram or multi-gated acquisition (MUGA)

Diffusion capacity of the lung for carbon monoxide (DLCO) >= 40% of predicted(corrected or uncorrected for hemoglobin per institutional standards)

Forced expiratory volume in 1 second (FEV1) >= 40% of predicted (corrected or uncorrected for hemoglobin per institutional standards)

Patient must have progressed or be refractory to prior anthracycline-containing chemotherapy (e.g. R-CHOP, DA-EPOCH-R, etc)

No more than 3 prior regimens for large cell component (e.g. one induction and two salvage therapies); monoclonal antibody alone or involved field/involved site radiotherapy do not count as lines of therapy

Prior use of ibrutinib is allowed unless patient has had disease progression while receiving ibrutinib

Patient must have chemosensitive disease as defined by at least a partial response to salvage therapy at their latest assessment

No major surgery =< 7 days prior to registration and no minor surgery =< 3 days prior to registration (with the exception of intravenous access placement, e.g. Hickman or peripherally inserted central catheter [PICC])

Not pregnant and not nursing; for women of childbearing potential only, a negative serum pregnancy test must be obtained within 14 days prior to registration

Women of childbearing potential must use adequate contraception from study start to one month after the last dose of protocol therapy; adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence; men must practice complete abstinence or agree to use an adequate contraception method from study start to one month after the last dose of protocol therapy

Patients should not require chronic use of strong CYP3A inhibitors or strong CYP3A inducers

Patients should not require concurrent therapeutic doses of steroids (> 20 mg of prednisone/day or equivalent) unless they need them for the indications; steroids should be discontinued for 14 days before starting protocol treatment

There is no prior history of acquired immunodeficiency syndrome (AIDS) defining conditions other than historically low CD4+ T-cell count or B-cell lymphoma

In the opinion of an expert in HIV disease, prospects for long-term survival are excellent were it not for the diagnosis of lymphoma

Use of HIV protease inhibitors as part of the anti-HIV regimen OR as a pharmacologic booster is not allowed

Zidovudine is not allowed

Once daily combination pills for HIV containing a pharmacologic booster such as cobicistat are not allowed

Patients with multi-drug resistant HIV are not eligible

Patients cannot have:

Active central nervous system or meningeal involvement by lymphoma; patients with a history of central nervous system (CNS) or meningeal involvement must be in a documented remission by cerebrospinal fluid (CSF) evaluation and contrast-enhanced magnetic resonance imaging (MRI) imaging for at least 91 days prior to registration

Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on any bone marrow biopsy prior to initiation of therapy

A known bleeding diathesis

Requirement for warfarin or similar vitamin K antagonists; these drugs are prohibited 28 days prior to the first treatment and throughout the trial

History of stroke or intracranial hemorrhage =< 6 months before treatment